Arpana Agrawal | PubMed Health

PubMed2026

Multi-ancestral genome-wide association study of chronic pain reveals widespread genetic correlations with mental and physical health traits.

Chronic pain (CP) is common and debilitating, affecting 12-40% of people worldwide. In this study, we conducted a genome-wide association study (GWAS) of CP in the All of Us Research Program across six genetic ancestries (Ntotal = 313 931, Ncase = 64 894, Ncontrol = 249 037). In the cross-ancestral meta-analysis, one locus on chromosome 3 reached genome-wide (GW) significance (α = 5E-08; lead SNP: rs3849410, p = 2.64E-08,). This same lead SNP, rs3849410, also reached GW significance in the European subsample (p = 7.45E-10) and in European females (p = 4.25E-08). Two additional loci, with lead SNPs rs7652179 and rs4760489, reached GW significance (p = 8.57E-09, and 3.07E-08, respectively) in European ancestry. Sex-stratified analyses revealed one locus on chromosome 11 (lead SNP: rs77607049) in males (p = 1.13E-08); in females, two other loci on chromosomes 11 (lead SNP: rs368001205) and 12 were also identified (lead SNP: rs80043169; p = 1.58E-08, 9.14E-09, respectively; p < 2.5E-08). CP was genetically correlated with psychiatric, physical, and immune traits, including anxiety (rg = 0.72, p = 2.00E-46), generalized addiction risk (rg = 0.38, p = 2.08E-17), higher C-reactive protein levels (rg = 0.36, p = 6.38E-22) and greater body mass index (rg = 0.43, p = 8.03E-47). This study represents one of the largest cross-ancestral investigations of the genetics of CP to date and demonstrates shared genetic effects between CP and multiple health conditions. PERSPECTIVE: This article presents multi-ancestral cross-sex and sex-stratified GWAS of chronic pain (CP). One significant cross-ancestral locus and 3 sex-specific loci were identified; a previously published locus for multisite CP met traditional genome-wide significance in the current European ancestry GWAS. This study identifies 4 novel genetic loci associated with CP.

Chronic pain↗

PubMed2026

Can Psychiatric Genetics Advance Without Incorporating a Life Course Perspective?

Psychiatric disorders unfold over the life course; however, genomic studies of these conditions overwhelmingly rely on phenotypes collected at a single time point, often in adulthood. Therefore, genome-wide association studies (GWASs) of psychiatric conditions may miss genetic variants with time-varying relevance to etiology, prevention, and treatment, such as those that influence trajectories of symptoms and behaviors, age at onset, course of treatment response, and the co-evolution of comorbidities. With recent advances in longitudinal biobanks and analytic tools, we posit that incorporating a life course perspective in psychiatric genetics will enable critically relevant insights into each of these areas of investigation. We propose that the current inconsistent portability of polygenic scores across age groups can be reconciled through the design of carefully considered longitudinal GWASs in age-diverse samples. Pioneering longitudinal GWASs in psychiatry have revealed novel genomic signals associated with time-dependent phenotypes that are distinct from those influencing lifetime diagnosis, suggesting that the study of longitudinal phenotypes will complement cross-sectional approaches and empower biological and therapeutic discoveries. Advances in post-GWAS functional annotation resources and analytic approaches now enable us to contextualize the genetic contributions to psychiatric disorders as dynamic age- and exposure-dependent processes. Although longitudinal GWASs pose unique challenges with regard to data availability, selection bias, and missing data, integrating temporality into psychiatric genetics at scale is now attainable and promises to reveal novel biology and therapeutic opportunities for psychiatric conditions.

Cohort study↗